The use of modified deoxyoligonucleotides for the inhibition of HIV replication via the binding to specific sequences of mRNA or DNA shows great promise. Most previous synthetic work in this area has focused on chiral analogs of the phosphate backbone. Neutral analogs are of special interest because of their possible ability to penetrate into cells by passive diffusion. This proposal has two aspects. The first is the development of synthetic methods for the facile synthesis of deoxyoligonucleotide analogs bearing a new neutral, achiral and stable internucleotide analog linkage, namely formacetal. Synthetic methods are proposed for the improved synthesis of formacetals. Promising chemistries will be adapted to polymer bound synthesis. The second aspect focuses on the in vitro hybridization of these modified analogs toward complementary RNA and their triplex formation ability with duplex DNA. The RNA interaction will be studied by classical thermal denaturation experiments and a new kinetic assay described in the preliminary data. The triplex interaction will be studied by footprinting assays on a novel DNA target reported in the preliminary data. The combined goal is the facile synthesis of neutral formacetal containing deoxyoligonucleotides which have enhanced sequence specific binding to HIV RNA and duplex DNA.